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PloS One 2013The glucocorticoid receptor (GR) regulates several physiological functions, including immune function and apoptosis. The HIV-1 virus accessory protein, viral protein R...
The progestin-only contraceptive medroxyprogesterone acetate, but not norethisterone acetate, enhances HIV-1 Vpr-mediated apoptosis in human CD4+ T cells through the glucocorticoid receptor.
The glucocorticoid receptor (GR) regulates several physiological functions, including immune function and apoptosis. The HIV-1 virus accessory protein, viral protein R (Vpr), can modulate the transcriptional response of the GR. Glucocorticoids (GCs) and Vpr have been reported to induce apoptosis in various cells, including T-cells. We have previously shown that the injectable contraceptive, medroxyprogesterone acetate (MPA) is a partial to full agonist for the GR, unlike norethisterone acetate (NET-A). We investigated the functional cross talk between the GR and Vpr in inducing apoptosis in CD4(+) T-cells, in the absence and presence of GCs and these progestins, as well as progesterone. By using flow cytometry, we show that, in contrast to NET-A and progesterone, the synthetic GR ligand dexamethasone (Dex), cortisol and MPA induce apoptosis in primary CD4(+) T-cells. Furthermore, the C-terminal part of the Vpr peptide, or HIV-1 pseudovirus, together with Dex or MPA further increased the apoptotic phenotype, unlike NET-A and progesterone. By a combination of Western blotting, PCR and the use of receptor- selective agonists, we provide evidence that the GR and the estrogen receptor are the only steroid receptors expressed in peripheral blood mononuclear cells. These results, together with the findings that RU486, a GR antagonist, prevents Dex-, MPA- and Vpr-mediated apoptosis, provide evidence for the first time that GR agonists or partial agonists increase apoptosis in primary CD4(+) T-cells via the GR. We show that apoptotic induction involves differential expression of key apoptotic genes by both Vpr and GCs/MPA. This work suggests that contraceptive doses of MPA but not NET-A or physiological doses of progesterone could potentially accelerate depletion of CD4(+) T-cells in a GR-dependent fashion in HIV-1 positive women, thereby contributing to immunodeficiency. The results imply that choice of progestin used in contraception may be critical to susceptibility and progression of diseases such as HIV-1.
Topics: Amino Acid Sequence; Apoptosis; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Cells, Cultured; Contraceptive Agents, Female; Dexamethasone; Gene Expression Regulation; Gene Products, vpr; HIV-1; Humans; Hydrocortisone; Medroxyprogesterone Acetate; Mifepristone; Molecular Sequence Data; Norethindrone; Norethindrone Acetate; Progesterone; Receptors, Estrogen; Receptors, Glucocorticoid; Signal Transduction
PubMed: 23658782
DOI: 10.1371/journal.pone.0062895 -
Infection and Immunity Nov 1971The effect of progesterone and testosterone on interferon production and on the viral infection-enhancing (VIE) activity of estrone and hydrocortisone was investigated....
The effect of progesterone and testosterone on interferon production and on the viral infection-enhancing (VIE) activity of estrone and hydrocortisone was investigated. Neither hormone interfered with interferon production. Progesterone reduced the VIE activity of estrone but not that of hydrocortisone. Testosterone had no effect on the VIE activity of either hormone. It is concluded that the lack of VIE activity by progesterone and testosterone may be related to their inabilities to suppress interferon production. The interference by progesterone with the VIE activity of estrone suggests that, in this system, the two hormones may affect common target cells.
Topics: Animals; Drug Interactions; Estrone; Female; Hydrocortisone; Interferons; Mice; Newcastle disease virus; Progesterone; Testosterone; Time Factors; Virus Diseases
PubMed: 5154893
DOI: 10.1128/iai.4.5.537-540.1971 -
Andrology Nov 2016In human spermatozoa, protein kinases have a role in the acrosome reaction (AR) induced by a variety of stimuli. However, there is disagreement or a lack of information...
In human spermatozoa, protein kinases have a role in the acrosome reaction (AR) induced by a variety of stimuli. However, there is disagreement or a lack of information regarding the role of protein kinases and phosphatases in the progesterone (P)-induced increase in intracellular calcium concentration ([Ca ] ). In addition, there are no studies regarding the role of Ser/Thr and Tyr phosphatases and there are contradictory results regarding the role of Tyr kinases in the P-induced acrosome reaction. Here, we performed a simultaneous evaluation of the involvement of protein kinases and phosphatases in the P-induced acrosome reaction and in the P-induced calcium influx. Motile spermatozoa were capacitated for 18 h and different aliquots were allocated to treated or control groups and then evaluated for their ability to undergo the acrosome reaction and to increase [Ca ] in response to P. The acrosome reaction was evaluated using Pisum sativum agglutinin (PSA)-FITC, and [Ca ] was evaluated using fura 2AM. At all of the concentrations tested, PKA inhibitors significantly reduced the percentage of the P-induced acrosome reaction (p < 0.001). However, only the highest concentrations of PKA inhibitors reduced the P-induced calcium influx; lower concentrations of PKA inhibitors did not affect it. Similar results were apparent for PKC inhibitors and for tyrosine kinase inhibitors. None of the Ser/Thr phosphatase inhibitors affected the P-induced acrosome reaction or the P-induced calcium influx, except for the PP2B inhibitors that significantly reduced the P-induced acrosome reaction without affecting calcium influx. Finally, the protein tyrosine phosphatase inhibitors significantly blocked the P-induced acrosome reaction and reduced the amplitude of the P-induced calcium transient (p < 0.001) as well as the amplitude of the plateau phase (p < 0.01). The data suggest that protein kinases and possibly PP2B have a role on the acrosome reaction at some point downstream of calcium entry and that Tyr phosphatases have a role on the acrosome reaction upstream of calcium entry.
Topics: Acrosome Reaction; Calcium; Humans; Male; Progesterone; Protein Kinase Inhibitors; Protein Kinases; Protein Tyrosine Phosphatases; Sperm Capacitation; Spermatozoa
PubMed: 27696749
DOI: 10.1111/andr.12234 -
Scientific Reports Nov 2017Sex hormones may contribute to the symptomatology of female-predominant temporomandibular disorders (TMDs) inflammatory pain. Pregnant women show less symptoms of TMDs...
Sex hormones may contribute to the symptomatology of female-predominant temporomandibular disorders (TMDs) inflammatory pain. Pregnant women show less symptoms of TMDs than that of non-pregnant women. Whether progesterone (P4), one of the dominant sex hormones that regulates multiple biological functions, is involved in symptoms of TMDs remains to be explored. Freund's complete adjuvant were used to induce joint inflammation. We evaluated the behavior-related and histologic effects of P4 and the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in the synovial membrane. Primary TMJ synoviocytes were treated with TNF-α or IL-1β with the combination of P4. Progesterone receptor antagonist RU-486 were further applied. We found that P4 replacement attenuated TMJ inflammation and the nociceptive responses in a dose-dependent manner in the ovariectomized rats. Correspondingly, P4 diminished the DNA-binding activity of NF-κB and the transcription of its target genes in a dose-dependent manner in the synovial membrane of TMJ. Furthermore, P4 treatment showed decreased mRNA expression of proinflammatory cytokines, and partially reversed TNF-α and IL-1β induced transcription of proinflammatory cytokines in the primary synoviocytes. Moreover, progesterone receptor antagonist RU-486 partially reversed the effects of P4 on NF-κB pathway. In conclusion, progesterone ameliorated TMJ inflammation through inhibition of NF-κB pathway.
Topics: Animals; Cytokines; Female; Humans; Mifepristone; NF-kappa B; Pregnancy; Pregnancy Complications; Progesterone; Rats; Rats, Sprague-Dawley; Signal Transduction; Synovial Membrane; Temporomandibular Joint; Temporomandibular Joint Disorders
PubMed: 29127312
DOI: 10.1038/s41598-017-15285-w -
Genes Apr 2020H3K27me3 is an epigenetic modification that results in the repression of gene transcription. The transcription factor RUNX1 (the runt-related transcription factor 1)...
H3K27me3 is an epigenetic modification that results in the repression of gene transcription. The transcription factor RUNX1 (the runt-related transcription factor 1) influences granulosa cells' growth and ovulation. This research uses ELISA, flow cytometry, EDU, ChIP-PCR, WB and qPCR to investigate steroidogenesis, cell apoptosis, and the proliferation effect of in porcine granulosa cells (pGCs) as regulated by H3K27me3. Decreased H3K27me3 stimulates the expression of steroidogenesis-related genes, including , , and , as well as prostaglandin. H3K27me3 transcriptionally represses here, whereas RUNX1 acts as an activator of , , and , promoting the production of androgen, estrogen, and prostaglandin, as well as increasing anti-apoptotic and cell proliferation activity, but decreasing progesterone. Both the complementary recovery of the H3K27me3 antagonist with the siRUNX1 signal, and the H3K27me3 agonist with the RUNX1 signal to maintain RUNX1 lead to the activation of , , , and here. Androgen and prostaglandin are significantly repressed but progesterone is markedly increased with the antagonist and siRUNX1. Prostaglandin is significantly promoted with the agonist and RUNX1. Furthermore, H3K27me3-RUNX1 affects the anti-apoptotic activity and stimulation of proliferation in pGCs. The present work verifies the transcriptional suppression of by H3K27me3 during antral follicular development and maturation, which determines the levels of hormone synthesis and cell apoptosis and proliferation in the pGC microenvironment.
Topics: Apoptosis; Cell Proliferation; Core Binding Factor Alpha 2 Subunit; Estrogens; Female; Follicle Stimulating Hormone; Gene Expression Regulation, Developmental; Granulosa Cells; Humans; Jumonji Domain-Containing Histone Demethylases; Ovulation; Progesterone; RNA, Messenger; Steroids
PubMed: 32365901
DOI: 10.3390/genes11050495 -
Brain Research Mar 2017Progesterone (P) binding to the intracellular progesterone receptors (PRs) plays a key role in epilepsy via modulation of GABA-A receptor plasticity in the brain. This...
Progesterone (P) binding to the intracellular progesterone receptors (PRs) plays a key role in epilepsy via modulation of GABA-A receptor plasticity in the brain. This is thought to occur via conversion of P to neurosteroids such as allopregnanolone, an allosteric modulator of GABA-A receptors. In the female brain, the composition of GABA-A receptors is not static and undergoes dynamic spatial changes in response to fluctuations in P and neurosteroid levels. Synaptic α2-containing GABA-A receptors contribute to phasic neuronal excitability and seizure susceptibility. However, the mechanisms underlying α2-subunit plasticity remain unclear. Here, we utilized the neurosteroid synthesis inhibitor finasteride and PR knockout mice to investigate the role of PRs in α2-subunit in the hippocampus. α2-Subunit expression was significantly upregulated during the high-P state of diestrous stage and with P treatment in wildtype and PR knockout mice. In contrast, there was no change in α2-subunit expression when metabolism of P into neurosteroids was blocked by finasteride in both genotypes. These findings suggest that ovarian cycle-related P and neurosteroids regulate α2-GABA-A receptor expression in the hippocampus via a non-PR pathway, which may be relevant to menstrual-cycle related brain conditions.
Topics: Animals; Diestrus; Female; Hippocampus; Mice, Inbred C57BL; Mice, Knockout; Neuronal Plasticity; Neurotransmitter Agents; Progesterone; RNA, Messenger; Receptors, GABA-A; Receptors, Progesterone; Up-Regulation
PubMed: 28137424
DOI: 10.1016/j.brainres.2017.01.030 -
Fertility and Sterility Nov 1991To report a preliminary study on the efficacy of a gonadotropin-releasing hormone antagonist (Nal-Glu) for preventing premature luteinizing hormone (LH) and progesterone...
OBJECTIVE
To report a preliminary study on the efficacy of a gonadotropin-releasing hormone antagonist (Nal-Glu) for preventing premature luteinizing hormone (LH) and progesterone (P) rise in controlled ovarian hyperstimulation using clomiphene citrate (CC) and human menopausal gonadotropin (hMG).
DESIGN
Participants in the study formed two groups. Both groups received CC-hMG and Nal-Glu. Group II differs from group I for receiving human chorionic gonadotropin (hCG) and blood samples for 10 days after the second Nal-Glu injection.
SETTING
Centre de Fecondation in Vitro, Hôpital Antoine Béclère.
PATIENTS
Eleven women 25 to 34 years of age and having normal menstrual cycles using barrier method of contraception not attempting pregnancies participated in the study.
INTERVENTION
Daily blood samples, pelvic ultrasound, and CC-hMG/Nal-Glu/hCG administration.
MAIN OUTCOME MEASURES
(1) Spontaneous LH surge and P rise, follicular growth, and plasma E2 levels in cycles with CC-hMG/Nal-Glu administration and (2) luteal phase after hCG injection in subjects previously treated with CC-hMG/Nal-Glu.
RESULTS
Plasma E2 level increased from 983 +/- 80 pg/mL (mean +/- SEM) on the day of the first Nal-Glu administration to 1,159 +/- 102 and 1,610 +/- 114 pg/mL (mean +/- SEM) 24 and 48 hours later. In 10 women, LH and P remained low for at least 96 hours after the first Nal-Glu administration. In one subject, plasma LH was already elevated at the time of the first Nal-Glu injection. In women who received hCG, plasma E2 and P reached a maximum of 1,258 +/- 313 pg/mL and 50.3 +/- 12.8 ng/mL (mean +/- SEM), respectively, on the 6th day of the luteal phase.
CONCLUSION
Our results suggest that timely Nal-Glu injections can prevent LH and P rise for at least 96 hours, in spite of increasing levels of plasma E2. Moreover, Nal-Glu had no adverse effect on the kinetic of E2 rise, the follicular growth, or on the post-hCG hormonal profile.
Topics: Adult; Estradiol; Female; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Menotropins; Menstruation; Ovarian Follicle; Ovarian Hyperstimulation Syndrome; Progesterone; Time Factors
PubMed: 1936328
DOI: 10.1016/s0015-0282(16)54666-4 -
The Journal of Cell Biology Nov 1995Milk production during lactation is a consequence of the suckling stimulus and the presence of glucocorticoids, prolactin, and insulin. After weaning the glucocorticoid...
Milk production during lactation is a consequence of the suckling stimulus and the presence of glucocorticoids, prolactin, and insulin. After weaning the glucocorticoid hormone level drops, secretory mammary epithelial cells die by programmed cell death and the gland is prepared for a new pregnancy. We studied the role of steroid hormones and prolactin on the mammary gland structure, milk protein synthesis, and on programmed cell death. Slow-release plastic pellets containing individual hormones were implanted into a single mammary gland at lactation. At the same time the pups were removed and the consequences of the release of hormones were investigated histologically and biochemically. We found a local inhibition of involution in the vicinity of deoxycorticosterone- and progesterone-release pellets while prolactin-release pellets were ineffective. Dexamethasone, a very stable and potent glucocorticoid hormone analogue, inhibited involution and programmed cell death in all the mammary glands. It led to an accumulation of milk in the glands and was accompanied by an induction of protein kinase A, AP-1 DNA binding activity and elevated c-fos, junB, and junD mRNA levels. Several potential target genes of AP-1 such as stromelysin-1, c-jun, and SGP-2 that are induced during normal involution were strongly inhibited in dexamethasone-treated animals. Our results suggest that the cross-talk between steroid hormone receptors and AP-1 previously described in cells in culture leads to an impairment of AP-1 activity and to an inhibition of involution in the mammary gland implying that programmed cell death in the postlactational mammary gland depends on functional AP-1.
Topics: Animals; Apoptosis; Base Sequence; Clusterin; Complement Inactivator Proteins; Dexamethasone; Endocrine Glands; Epithelial Cells; Female; Genes, jun; Glucocorticoids; Glycoproteins; Mammary Glands, Animal; Matrix Metalloproteinase 3; Metalloendopeptidases; Mice; Mice, Inbred Strains; Molecular Chaperones; Molecular Sequence Data; Neoplasm Proteins; Progesterone; Transcription Factor AP-1
PubMed: 7490285
DOI: 10.1083/jcb.131.4.1095 -
FEBS Letters Aug 2005We investigated whether GABA activates phospholipase A2 (PLA2) during acrosomal exocytosis, and if the MEK-ERK1/2 pathway modulates PLA2 activation initiated by GABA,...
We investigated whether GABA activates phospholipase A2 (PLA2) during acrosomal exocytosis, and if the MEK-ERK1/2 pathway modulates PLA2 activation initiated by GABA, progesterone or zona pellucida (ZP). In guinea pig spermatozoa prelabelled with [14C]arachidonic acid or [14C]choline chloride, GABA stimulated a decrease in phosphatidylcholine (PC), and release of arachidonic acid and lysoPC, during exocytosis. These lipid changes are indicative of PLA2 activation and appear essential for exocytosis since inclusion of aristolochic acid (a PLA2 inhibitor) abrogated them, along with exocytosis. GABA activation of PLA2 seems to be mediated, at least in part, by diacylglycerol (DAG) and protein kinase C since inclusion of the DAG kinase inhibitor R59022 enhanced PLA2 activity and exocytosis stimulated by GABA, whereas exposure to staurosporine decreased both. GABA-, progesterone- and ZP-induced release of arachidonic acid and exocytosis were prevented by U0126 and PD98059 (MEK inhibitors). Taken together, our results suggest that PLA2 plays a fundamental role in agonist-stimulated exocytosis and that MEK-ERK1/2 are involved in PLA2 regulation during this process.
Topics: Acrosome Reaction; Animals; Arachidonic Acid; Aristolochic Acids; Diglycerides; Enzyme Activation; Exocytosis; Extracellular Signal-Regulated MAP Kinases; Female; Guinea Pigs; MAP Kinase Signaling System; Male; Mitogen-Activated Protein Kinase Kinases; Phospholipases A; Phospholipases A2; Progesterone; Protein Kinase C; Spermatozoa; Zona Pellucida; gamma-Aminobutyric Acid
PubMed: 16098515
DOI: 10.1016/j.febslet.2005.06.090 -
The Journal of Clinical Endocrinology... Nov 2018Fos null mice failed to ovulate and form a corpus luteum (CL) even when given exogenous gonadotropins, suggesting that ovarian Fos expression is critical for successful...
CONTEXT
Fos null mice failed to ovulate and form a corpus luteum (CL) even when given exogenous gonadotropins, suggesting that ovarian Fos expression is critical for successful ovulation and CL formation. However, little is known about FOS in the human ovary.
OBJECTIVES
To determine the expression, regulation, and function of FOS in human periovulatory follicles.
DESIGN/PARTICIPANTS
Timed periovulatory follicles were obtained from normally cycling women. Granulosa/lutein cells were collected from in vitro fertilization patients.
MAIN OUTCOME MEASURES
The in vivo expression after human chorionic gonadotropin (hCG) administration and in vitro regulation of FOS, JUN, JUNB, and JUND was evaluated at the mRNA and protein level. Binding of progesterone receptor (PGR) and FOS to their target genes was assessed by chromatin immunoprecipitation analyses. Prostaglandin E2 (PGE2) and progesterone were measured.
RESULTS
The expression of FOS, JUNB, and JUND drastically increased in ovulatory follicles after hCG administration. In human granulosa/lutein cell cultures, hCG increased the expression of FOS and JUN proteins. Inhibitors of PGR and epidermal growth factor (EGF) receptors reduced hCG-induced increases in the expression and phosphorylation of FOS. PGR bound to the FOS gene. A selective FOS inhibitor blocked hCG-induced increases in PGE2 and the expression of prostaglandin (PG) synthases and transporters (PTGES, SLCO2A1, and ABCC1). FOS bound to the promoter regions of these genes.
CONCLUSIONS
The increase of FOS/activator protein 1 in human periovulatory follicles after hCG administration is mediated by collaborative actions of PGR and EGF signaling and critical for the upregulated expression of key ovulatory genes required for the rise in ovulatory PG in human granulosa cells.
Topics: Adult; Benzophenones; Cells, Cultured; Chorionic Gonadotropin; Dinoprostone; Epidermal Growth Factor; Female; Humans; Isoxazoles; Mifepristone; Ovarian Follicle; Ovulation; Primary Cell Culture; Progesterone; Proto-Oncogene Proteins c-fos; Quinazolines; RNA, Small Interfering; Receptors, Progesterone; Signal Transduction; Tyrphostins; Up-Regulation
PubMed: 30124866
DOI: 10.1210/jc.2017-02532